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Meet a Broad physician-scientist: Adam Bass

Perhaps no one has a more complete picture of a disease than a physician-scientist does. Take Adam Bass, who this week published, with his co-authors, a study on the genome sequence of esophageal adenocarcinoma (EAC), a deadly cancer that starts in the lower esophagus: as a physician, Bass has cared for patients afflicted with EAC, and has seen its devastating effects. As a research scientist, Bass has also seen the inner workings of the disease, and is hunting for its vulnerabilities. His research is focused on identifying the molecular processes driving EAC, with the goal of developing effective therapies that he and other clinicians may one day use to treat patients.

Bass, who is an associate member in the Broad’s Cancer Program and an assistant professor at Dana-Farber Cancer Institute, first became interested in developing targeted cancer therapies while completing his clinical training. He witnessed the “frustratingly slow progress” being made in the care of hard-to-treat tumors using the traditional method of mixing and matching chemotherapies; it was a “one-size-fits-all” approach that aimed to treat tumor types without taking into account what might work best for individual patients.

By the time Bass started his postdoctoral fellowship in the lab of Broad senior associate member Matthew Meyerson in 2006, that approach to cancer therapy had started to change. Targeted therapies such as Iressa and Gleevec were being used with some success to treat cancers with specific genetic underpinnings, and advances in genomic sequencing were making it easier to identify new, potential targets for cancer treatments. Working in the Meyerson lab, where the research focus was on cancer genomics, Bass got to see this shift firsthand.

“You could see where the field should be moving,” he said, “and I could see how Matthew Meyerson and others were pushing it in the direction of targeted therapeutics, especially in the field of lung cancer.”

Adam Bass, MD

At the same time, Bass didn’t see as much progress being made with other tumor types. EAC tumors, for instance, had been relatively neglected, despite a startling 600% increase in cases over the past 30 years.

“I became interested in gastrointestinal oncology because it involved a group of very common and deadly tumors that hadn’t received nearly enough research attention,” Bass explained. “It seemed a place where help was clearly needed.”

Today, Bass runs a lab that collaborates with Broad colleagues on gastrointestinal cancer genome research, and investigates genes that emerge from those studies. An overarching goal of his lab is to determine how best to tailor therapies for patients based on the particular vulnerabilities of their cancer. Ultimately, he intends to work with colleagues at Dana-Farber to design clinical trials on targeted cancer therapeutics based upon his lab’s research.

The EAC genome sequencing study, which Bass led alongside co-senior author Gad Getz, director of cancer genome computational analysis at the Broad, was published this week in Nature Genetics. The study uncovered a pattern of genetic mutations unique to EAC: a change in the As, Cs, Gs, and Ts of the genetic code in which, when two “A” bases appear in a row, the second “A” is frequently mutated into a “C.” These A to C changes accounted for about a third of the mutations found in the tumors. The team suspects that these mutations may be triggered by exposure to acid reflux, a condition that’s on the rise in the general population and is considered to be a likely contributor to the recent increase in EAC cases.

The team also identified over two-dozen genes that are frequently altered in EAC. Two of those genes – ELMO1 and DOCK2 – are known to work together to activate a third gene, RAC1, which has previously been implicated in melanoma and has been shown to make cells more invasive. It’s a finding that might help explain why EAC tumors tend to spread at an earlier stage than many other cancers, and why the disease might be so deadly.

Together, the findings may help scientists understand what is driving EAC, and potentially lead to better screening and treatment. At the same time, the breadth of the findings underscores the complexity of the disease. Additional work will need to be done in order to understand the roles these genes and mutations play in the cancer’s progression, and to identify which of them might be useful therapeutic targets.

“Determining the various pathways that cause EAC and developing targeted therapies for each possible cause will be a challenge for years to come,” Bass explains, “but this research gives us a roadmap so that we can start to design clinical trials that group patients based on their genetic biomarkers, and then treat them with drugs that we suspect are more likely to work based on the biology of their cancer.”

Bass notes that a clear goal of his work as a physician-scientist is to bring some of the hypotheses developed in his lab into the clinic. He also suspects that, as his lab becomes more active in the development of clinical therapies, what’s happening in the clinic will also inform his team’s genomics work, possibly leading to new avenues of research.